The relation between induction of both single GST-P positive hepatocytes and foci was assessed after treatment with 0.015% Trp-P-1, 0.05% Glu-P-2, 0.03% IQ, 0.03% MeIQ, 0.04% McIQx alone or in combinations of all five at 1/5 or 1/25 of these individual dietary doses for 6 weeks, partial hepatectomy being performed at week 1. A good correlation between induction of single cells and focal lesions was observed. Additional analysis of covalent binding of heterocyclic amines to rat liver DNA by the 32P-postlabeling method revealed a good fit with yield of preneoplastic lesions. The results thus suggest that DNA adducts resulting from exposure to heterocyclic amines play an important role in the earliest stages of chemical carcinogenesis in the rat liver.
The goitrogenic actions of 5-substituted 3-amino-l, 2, 4-triazoles, 3-amino-5-mercapto-l, 2, 4-triazole (AMTZ), 3-amino-1, 2, 4-triazole-5-carboxylic acid (ATZC), 3, 5-diamino-l, 2, 4-triazole (DTZ), 3-amino-5-methylthio-l, 2, 4-triazole (AMTTZ), and 3-amino-1, 2, 4- triazole (ATZ) were compared in rats. ATZ, AMTZ, ATZC, and DTZ inhibited the thyroid peroxidase (TPO)-catalyzed oxidation of guaiacol in vitro, exhibiting the order of antithyroid activity ATZ>AMTZ>ATZC>DTZ. In in vivo experiments, ATZ, ATZC, or AMTZ inhibited TPO activity, and induced goiter accompanied by decrease in serum thyroid hormone and increase in serum thyroid-stimulating hormone in rats. These antithyroid activities were shown in order of ATZ>ATZC>AMTZ. The TPO inhibitory action of ATZC in vivo was weaker than that of AMTZ, but it was more persistent than AMTZ. The anti-TPO action of DTZ disappeared in vivo, and AMTTZ showed no effects in vitro and in vivo. These results show that ATZC, AMTZ, and DTZ potentially have the anti-TPO activity like as ATZ and the 5-position site of ATZ would have a very important meaning to determine the antithyroid action of ATZ. In addition, the results strongly suggest that the anti-thyroid action depends on the substitute but not on the parental compound.
The effect of adriamycin-oxidized dextran (ADM-OXD) on sinusoidal structure was studied using male Wistar rats. Ultramorphological monitoring and biochemical monitoring were performed after massive administration of ADM-OXD at a dose of 60mg/kg. Destruction of sinusoidal structure followed by damage to hepatocytes was subsequently observed. As early as 12 to 24 hours after ADM-OXD administration, endothelial cells and Kupffer cells were found to be degenerative or necrotic under transmission electron microscopic observation, and a tendency to disintegrate was observed in the sinusoidal wall structure. Scanning electron microscopic observation at 24 hours after administration revealed the destruction of the fenestral structure of endothelial cells, while morphological necrosis of hepatocytes and pronounced elevation of serum transaminase activity were noted at 48 hours. Mild endotoxemia was induced from soon after drug injection. In connection with this, serum complement activity began to decrease and was found to have fallen markedly at 24 hours, indicating significant consumption of alternative complement elements. ADM-OXD-induced hepatic dysfunction was found to be exacerbated by treatment with extrinsic lipopolysaccharide (LPS) and abated by treatment with endotoxin neutralizing agent (polymyxin B). Complement activity inhibitor also significantly abated hepatotoxicity. In situ liver perfusion of nitro bule tetrazolium (NBT) revealed that ADM-OXD administration did not produce stimulation of Kupffer cells. Anti-TNF-a treatment was found to have no abating effect on ADM-OXD-induced hepatic dysfunction. Biochemically, complement activation through endotoxemia may be assumed to participate in inducing hepatocyte damage, while mor-phologically, it is likely that destruction of the sinusoidal wall structure effects the susceptibility of hepatocytes to extrinsic environmental change.
The effect of T-2 mycotoxin on hepatocyte proliferation was investigated in mice using two models of hepatocyte regeneration, i.e. 2/3 partial hepatectomy (Ph) and CCl4-intoxication (CCl4). At 2 days after Ph or CCl4, mice were given T-2 toxin (2 or 4mg/kg, po). Five mice each were killed daily up to 7days after Ph or CCl4, and they were injected with BrdU (100mg/kg, ip) at I hour before sacrifice. T-2 toxin significantly delayed the recovery of liver weight loss after Ph Or CCl4, and it also significantly delayed the reduction in size of centrilobular hepatocyte necrosis after CCl4. In addition, T-2 toxin significantly depressed BrdU-uptake by hepatocytes in the early days after Ph or CCl4. It can be said that T-2 toxin depressed the proliferation of hepatocytes, resulting in the delay of recovery of liver weight loss. This seems to be related to the inhibitory effect of T-2 toxin on nuclear acid synthesis of hepatocytes.
Gardenia yellow (GY) is a widely used natural yellow colorant for foods and clothing. In this study, we have examined the sub-chronic and chronic effects of GY in mice. Both sexes of C57BL/ HeN mice of six weeks old were used. GY was dissolved in distilled water and orally administered. In the sub-chronic study, 0, 0.05, 0.1, 0.2, 0.4, 0.8, and 1.6% of GY were given to mice and they were observed for 12 weeks. During this period, there were no abnormal changes detected in survivals, body weight increases or pathology of organs. It was concluded that GY had no toxicity up to 1.6% in drinking water. The concentrations of 0, 0.2 and 0.8% of GY were chosen for the further carcinogenicity study by observing for 95 weeks. In this chronic toxicity study, there was a 4.5 to 15.4% development of plasmacytoma in the mesenteric lymph nodes that has been known to occur spontaneously in C57BL mice. The pituitary and liver tumors were also noted regardless of the GY doses. The unique observation in this experimental series is the development of hepatosis that is characterized with enlarge-ments of liver, spleen, kidney, and lymph nodes, although they were not related to the doses of GY. These findings were rather systemic and this syndrome may be categorized as amyloidosis. The present study did not show any carcinogenicity or other chronic disorders by GY.
The possibility of producing colon tumors by administration of 1, 2-dimethylhydrazine (DMH) to (C3H×MSM) F1 hybrids of inbred and wild strains mice, was investigated in an attempt to establish an experimental model for detection of DNA polymorphism markers for colon carcinogenesis in mice. DMH at doses of 0, 10, and 15mg/kg body weight was given intra-peritoneally once a week for 10 weeks and the experiment was terminated 46 weeks after the initial administration. The first colon tumors appeared after 30 weeks and final incidencs reached 38.5% in female mice receiving 10 mg DMH and 90.9 and 100%, respectively, in male and female mice receiving 15mg DMH/kg body weight. Tumors were multiple, mainly located in the distal colon and primarily adenomas and adenocarcinomas.
Monoclonal antibody against colon cancer inducing virus particles of WF-Osaka rat strain was yielded. Using monoclonal antibody, solid-phase immune electron microscopic study was carried out. Viable virus particles were disclosed from the supernatant of S3 medium, fixed by means of ultra microwave for 2 minutes. The size of these particles was approximately 40 to 50 nm in diameter, and the particles showed numerous spikes on the surface. Furthermore, transmission electron microscopy of transplantable gastric carcinoma and lymphoma revealed virus particles in their cytoplasm. We believe that this is the first report of virus inducing intestinal cancer among animals.
The carcinogenicity of commercial glycine (GL) was assessed in groups of 50 male and 50 female F344 DuCrj rats by application in the drinking water at levels of 0. 2.5 or 5.0% for 108 wk. A dose-dependent reduction in the mean final body weights of rats was observed with GL, the incidences of necrosis in the renal papillae also being increased by the treatment. Thus while the controls were negative, necrosis was observed in 3 of 40 males and 10 of 31 females given 5.0% GL, and 2 of 45 males and 14 of 46 females receiving 2.5% GL. Incidences of urinary bladder papilloma were 2 in 31 females (6%) given 5.0% GL and 4 in 46 female (8%) given 2.5% GL. One renal cell tumor was noted in a male receiving 5.0% GL, but no precancerous renal cell lesions. One pelvic transitional cell carcinoma was also found in a control male.
Inherited hydrocephalic rat develops irritability and/or pareses during progression of hydrocephalus in associated with hemorrhages in dorsal root ganglia and spinal cord which transmit the sensory information. The strains of inherited hydrocephalic rats, HTX and Hyd, were employed to investigate sensory disorder, especially nociception due to a cut incision or formalin injection to the foot pad of left hindlimb. The rats were perfused after three hours and Fos-like immunoreactivities were examined (FLI) in the neurons of dorsal horn in spinal lumbar cord (L4). 1) FLI positive cells were seen more expressive in the hydrocephalic rats without or with hemor-rhage in dorsal root ganglia than in the normal appearing rats. The hydrocephalic rats with spinal pericanal hemorrhage and ganglia hemorrhage showed less FLI positive cells than normal appearing rats. 2) FLI positive cells were moderately expressed in the deeper lamina in the hydrocephalic rats. 3) Dead neurons were scattered in the thalamic ventral posterior nuclei and medial geniculate bodies in the hydrocephalic rat. These results suggested that inherited hydrocephalic rats are hyperalgesic and FLI is morphologically a useful tool expressed by sensory disorder.
Repeated injection of thiophene induced clinical signs to grooming, trunkal ataxia, or tonic convulsion and the signs are similar to those of cerebellar degeneration by methyl mercury poisoning. The rats disclosed by PAS reaction in inferior colliculus, and disorder in auditory brainstem response. In thiophene poisoned rats have arranged an immunohistochemical (Fos immunoreactivity) and histopathological methods to evaluate the correlation between those signs and lesions. 1) Fos-like immunoreactivity (FLI) in the central nervous system was distributed the characteristic associated with trunkal ataxia and/or tonic convulsion. 2) FLI positive cells disclosed nerve cells by rim of the necrotic regions (penumbra) in the cerebellum. 3) Neuronal degeneration was scattered in the resemblance area in contralateral hemisphere of the same rat that had displayed continuous and excessive FLI positive cells. 4) Marchi stain and FLI displayed how it is dependent on the degeneration of the cerebellar nucleus, the red nucleus, and the dorsal lateral funiculus, to be related into rubrospinal tracts. These results showed that FLI is a useful tool for check to the early phase of the lesion and transsynaptic lesion associated with clinical signs induced by a neurotoxic agent.